Drug addiction is a national health problem. Interestingly, men and women have different sensitivities to the development of cocaine addiction that are unrelated to differences in the pharmacokinetics of the drug. There is substantial literature pointing to estrogen as a critical chemical signal affecting cocaine sensitization in the female. The studies in this proposal are designed to elucidate estrogen's mechanism of action in cocaine sensitization. It is hypothesized that estrogen facilitates cocaine sensitization by: (1) sensitizing components of the mesocorticolimbic system to repeated cocaine administration (2) altering the interaction between the opioid and dopaminergic systems. Previous studies from our laboratory indicate that estrogen and opioids interact to regulate the behavioral response to cocaine in the female rat. To investigate the mechanisms involved we have formulated the following specific aims: (1) It is hypothesized that estrogen facilitates cocaine sensitization by blunting cocaine-induced neuronal activation in rostral mesocorticolimbic brain structures such as the nucleus accumbens (NAc) and prefrontal cortex. (2 and 3) It is anticipated that repeated cocaine enhances mu and decreases kappa opioid receptor function in the nucleus accumbens. To address specific aim 1, ovariectomized rats without (OVX) and with (OVX-EB) estrogen will be injected for 5 days with cocaine hydrochloride (15 mg/kg), challenged on day 13 with the same dose of cocaine and brain activity monitored by fMRI. To address specific aims 2 and 3, we will measure changes in mu and kappa opioid receptor binding in OVX and OVX-EB rats in response to acute and repeated cocaine and after withdrawal and reinstatement. An additional group of animals will be treated with specific mu and kappa opioid agonists and antagonists during repeated cocaine administration and after reinstatement and tested for behavioral sensitization. The progressive daily increase in locomotor activity elicited by the same dosage of cocaine will be used as an indicator of cocaine sensitization. Opioid ligands that induce changes in behavioral sensitization will be used in experiments that image cocaine-induced changes in BOLD signal by functional MRI (fMRI). At the conclusion of the in vivo studies, the brains will be studied for assessment of opioid (mu and kappa) receptors by regular and functional autoradiography. The proposed research is innovative because it capitalizes on the new technology of fMRI to identify sites in the brain that respond to acute and repeated cocaine administration. The results obtained will be significant because they will provide neurobiological data for the development of new therapeutic strategies in the treatment of drug addiction taking into consideration the differences in the physiology and biochemistry of men and women.